Roles of Myotubularin PI 3-phosphatases in Demyelinating Peripheral Neuropathy

肌管蛋白 PI 3-磷酸酶在脱髓鞘性周围神经病中的作用

• 批准号: 7919117
• 负责人: FRED L ROBINSON
• 金额: $ 24.89万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7919117
• 关键词: Peripheral Nervous System Diseases; Phosphoric Monoester Hydrolases; Role; myotubularin

The Candidate, Dr. Fred Robinson, has been training for the last four years as a fellow in the laboratory of Dr. Jack Dixon. Dr. Dixon's Laboratory is in the Department of Pharmacology at the University of California San Diego (UCSD) School of Medicine. UCSD is a renowned research institution, particularly strong in the fields of neuroscience, signal transduction and cancer biology. Dr. Dixon is a world leader in the study of protein and lipid phosphatases. The Candidate has established a fledgling research program focused on understanding how mutations in myotubularin family phosphoinositide (PI) 3-phosphatases lead to Charcot-Marie-Tooth (CMT) peripheral neuropathy. CMT is the most common inherited neurological disorder, affecting about 1 in 2000 in the United States. CMT causes progressive degeneration of the muscles of the extremities and loss of sensory function. Type 4B CMT (CMT4B) is a severe form of the disease in which the myelin sheaths of peripheral nerves are abnormal. Mutations in the genes for either myotubularin related protein 2 (MTMR2) or MTMR13 cause CMT4B. The Candidate recently demonstrated that the MTMR2 and MTMR13 PI 3-phosphatases form a membrane-associated complex capable of regulating 3-phosphoinositides. As loss of either MTMR2 or MTMR13 is sufficient to cause CMT4B, MTMR13 is likely an essential regulator of MTMR2. To further probe the relationship between MTMR2 and MTMR13, the Candidate has generated Mtmrl 3-deficient mice. The specific aims of the proposal are (1) Validate Mtmrl 3-deficient mice as a model of CMT4B disease, (2) Examine the impact of loss of Mtmrl 3 on Mtmr2 function, and (3) Determine how 3-phosphoinositide homeostasis and endosomal-lysosomal trafficking are perturbed in Mtmrl 3-deficient Schwann cells. Understanding how the Schwann cell endosomal-lysosomal pathway is altered by the dysregulation of 3- phosphoinositides may allow us to consider pharmacological modulation of the pathway as a therapeutic strategy. The initial phase of the work (1-2 years) will be carried under Dr. Dixon's supervision. The Candidate will also be mentored by Dr. Katerina Akassoglou, an expert in peripheral nerve biology and demyelination. This phase will focus on characterization of Mtmrl 3-deficient mice and on other aspects of the project for which key training is available at UCSD. Later, as an independent investigator, the Candidate will continue studying Mtmrl 3-deficient mice, focusing more specifically on Schwann cell biology.

候选人弗雷德罗宾逊博士在过去的四年里一直在杰克狄克逊博士的实验室接受培训。狄克逊博士的实验室位于加州圣地亚哥大学（UCSD）医学院的药理学系。UCSD是一个著名的研究机构，在神经科学，信号转导和癌症生物学领域特别强大。狄克逊博士是蛋白质和脂质磷酸酶研究的世界领导者。候选人已经建立了一个羽翼未丰的研究计划，重点是了解肌管蛋白家族磷酸肌醇（PI）3-磷酸酶的突变如何导致Charcot-Marie-Tooth（CMT）周围神经病变。CMT是最常见的遗传性神经系统疾病，在美国影响约1/2000。CMT导致四肢肌肉的进行性变性和感觉功能的丧失。4 B型CMT（CMT 4 B）是一种严重的疾病形式，其中周围神经的髓鞘异常。肌管蛋白相关蛋白2（MTMR 2）或MTMR 13基因突变导致CMT 4 B。候选人最近证明，MTMR 2和MTMR 13 PI 3-磷酸酶形成能够调节3-磷酸肌醇的膜相关复合物。由于MTMR 2或MTMR 13的缺失足以导致CMT 4 B，因此MTMR 13可能是MTMR 2的重要调节剂。为了进一步探索MTMR 2和MTMR 13之间的关系，候选人已经产生了Mtmr 13缺陷型小鼠。该提案的具体目的是（1）将Mtmrl 3缺陷型小鼠作为CMT 4 B疾病的模型，（2）检查Mtmrl 3缺失对Mtmr 2功能的影响，和（3）确定Mtmrl 3缺陷型雪旺细胞中3-磷酸肌醇稳态和内体-溶酶体运输如何被扰乱。了解雪旺细胞内体-溶酶体途径是如何通过3-磷酸肌醇的失调而改变的，可能使我们能够考虑将该途径的药理学调节作为治疗策略。 工作的初始阶段（1-2年）将在狄克逊博士的监督下进行。候选人还将接受周围神经生物学和脱髓鞘专家Katerina Akassoglou博士的指导。这一阶段将侧重于Mtmrl 3缺陷小鼠的表征以及该项目的其他方面，其中关键培训可在UCSD获得。之后，作为一名独立的研究者，候选人将继续研究Mtmrl 3缺陷小鼠，更具体地专注于许旺细胞生物学。